Primary Amyloidosis. Kihyun Kim Div. of Hematology/Oncology, Dept. of Medicine, Sungkyunkwan Univ. School of Medidine Samsung Medical Center

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1 Primary Amyloidosis Kihyun Kim Div. of Hematology/Oncology, Dept. of Medicine, Sungkyunkwan Univ. School of Medidine Samsung Medical Center

2 Systemic Amyloidosis A group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. At least 28 different proteins Localized (Alzheimer s and Creutzfeldt- Jakob diseases) vs. Systemic

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4 N Engl J Med 2003;349:583-96

5 Mechanism of Tissue Damage Incompletely understood a physical, mechanical replacement of parenchymal tissue by amyloid deposits seems to be insufficient. Increasing evidences of the role of prefibrillar oligomers, rather than the fibrillar form Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells (improvement of NTproBMP without change of amyloid deposits in myocardium) The relative impact of amyloid deposits or prefibrillar aggregates on cytotoxicity and tissue dysfunction may vary among types of amyloidosis and among organs.

6 Most Common Types of Systemic Amyloidoses Type Abbr. Precursor Site of Synthesis Syndrome and Organs Involved Immunoglobulin light chain amyloidosis Reactive amyloidosis Senile systemic amyloidosis Transthyretin amyloidosis AL Monoclonal light chain BM plasma cells AA Serum amyloid A Liver SSA ATTR Transthyretin wild type Variant TTR >100 mutations Liver > 90% Liver > 90% Primary, in 10%-15% of patients with MM H, K, L, GI, PNS, ANS, ST Secondary to chr. inflammation, infection, or certain neoplasia K, GI, L, ANS, spleen, Age-related, usually males (age > 65 years) Primarily cardiac involvement Hereditary H, PNS, ANS, eye, leptomeninges, rarely kidneys Fibrinogen amyloidosis AFib Variant fibrinogen -chain Liver Hereditary Involvement of kidneys Apolipoprotein A-I amyloidosis AApoAI Variant apolipoprotein AI Liver, intestine Hereditary H, K, L, skin, larynx, testes J Clin Oncol 29:

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8 N Engl J Med 2003;349:583-96

9 Primary Amyloidosis The most common form of systemic amyloidosis incidence of 8.9 per million person-years caused by a neoplastic plasma cell or B- cell clone

10 2010 ASH education

11 Annals of Oncology 19 (Supplement 4): iv63 iv66, 2008

12 Annals of Oncology 19 (Supplement 4): iv63 iv66, 2008

13 When should the diagnosis of AL be considered? nondiabetic nephrotic syndrome nonischemic cardiomyopathy with an echocardiogram showing concentric hypertrophy increase of NTproBNP in the absence of primary heart disease hepatomegaly or increase of alkaline phosphatase without an imaging abnormality peripheral and/or autonomic neuropathy unexplained facial or neck purpura macroglossia

14 Diagnostic algorithm for systemic amyloidosis. J Clin Oncol 29:

15 Diagnosis and Differential Diagnosis IF (s), IF (u), serum-free light chain assay bone marrow biopsy plasma cell proliferation the stroma or blood vessels will be positive for amyloid in >60% of patients Congo red staining of subcutaneous fat aspiration positive in 90% of patients biopsy of the labial salivary glands may detect amyloid deposits in 50% of patients Involved organ biopsy

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18 MISDIAGNOSIS OF HEREDITARY AMYLOIDOSIS AS AL (PRIMARY) AMYLOIDOSIS N Engl J Med 2002; 346:

19 Making the Diagnosis and Getting the Type Right the possibility that the amyloidosis may be secondary or familial with an incidental monoclonal gammopathy of undetermined significance Immunohistochemistry or immunogold assay. Laser microdissection with mass spectrometry (LMD/MS) can confirm the amyloid protein composition and is considered the standard for typing the protein subunit in amyloid deposits. now the gold standard for typing amyloid, enabling precise identification of type in over 98% of cases captures all of the chaperone and fellow-traveler elements in amyloid deposits, as well as the identity of the protein in the fibrils. DNA sequencing of genes related to hereditary variants is also useful, particularly for confirming proteomic findings and subsequent screening of kin.

20 Immunohistochemistry

21 Vrana, J. A. et al. Blood 2009;114:

22 Laboratory Investigation (2008) 88,

23 Assessment of Organ Involvement

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25 Prognosis and Staging The extent of cardiac involvement. Echocardiography Serum cardiac biomarkers Serum troponin T and N-terminal pro brain natriuretic peptide (NT-proBNP) cutoff values of mcg/l troponin T and 332 pg/ml NTproBNP, Stage I, both biomarkers low (33% incidence); Stage III, both values high (30% incidence); or Stage II, only 1 marker high (37% incidence). median survivals are 26.4, 10.5, and 3.5 months, respectively, for Stages I, II, and III. Stage III patients should be excluded from SCT studies. poor candidates for clinical trials of standard agents [38]. Response to treatment, percentage of bone marrow plasma cells, the Ig free light chain level at diagnosis, the number of organs involved and the serum uric acid level have all been associated with prognosis. Many other prognostic factors reflecting burden of disease and organ dysfunction have been proposed but not validated prospectively.

26 Proportion surviving 1 Stage I-t Stage II-t Stage III-t Schedule N Deaths MS, months Stage I-t Stage II-t Stage III-t P < Time (months)

27 Evaluation of the cytogenetic aberration Blood. 2008;111: Bryce AH et al. Haematologica. 2009;94(3):380-6.

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29 Organ Response & Hematologic response Gertz MA, et al. Am J Hematol 2005;79:

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31 Criteria for Hematologic and Organ Response The definition of a measurable absolute concentration of involved FLC (iflc) was revised from involved >100 mg/l to a >50 mg/l difference between involved and uninvolved FLC (dflc), as the new threshold. Amyloid 17:48-49, 2010 (suppl 1; abstr CP-B)

32 Treatment Overall survival Median OS; 31 Mo Progression-free survival Median PFS; 27 Mo Blood Dec 1;104(12):

33 Melphalan and High-Dose Dexamethasone Median survival; 5.1 years Palladini G, Blood. 2007;110:787 Blood. 2010;116(4):

34 Autologous stem cell transplant Boston data (n=312) Median survival; 4.6 years Skinner et al, Ann Intern Med. 2004;140:85 Bone Marrow Transplantation (2004) 34,

35 Prognostic markers in patients with primary systemic amyloidosis undergoing ASCT Cardiac involvement Ann Intern Med. 2004;140:85 Absolute values of FLC Blood Apr 15;107(8): Achievement of response after ASCT Haematologica 2007; 92:

36 High-Dose Melphalan versus Melphalan plus Dexamethasone for AL Amyloidosis median OS 56.9 months median OS 22.2 months poor results with high-dose melphalan no selection bias d/t referral to tertiary center the delay before initiation of therapy the possible enrollment of patients with advanced disease N Engl J Med 2007;357:

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38 Thalidomide Novel Agents hematologic responses: 48%, 19% CR, treatment-related toxicity was frequent, and the agent was poorly tolerated. Thalidomide/M/DEX TCD 8 HR & 4 OR in 22 patients HR 74% and CR 21%, Median overall survival 41 months, median PFS 32 months, and treatment related mortality was 3%. stem-cell sparing, unlike MDex, but the side effects of thalidomide, particularly neuropathy, bradycardia, and worsening congestive heart failure, remain significant in AL. Current recommendations suggest that thalidomide be started at a dose not higher than 50 mg. Dose can be increased if tolerated. notable confounding aspect of IMiD therapy in AL is a rise in cardiac biomarkers that does not correlate with worsening cardiac status or hematologic progression.

39 Lenalidomide Lenalidomide/ Dex Novel Agents Toxicities include cytopenias, rash, fatigue, and cramps. 1 st two studies HR 41% and the median response duration and overall survival were 19.2 and 31 months, respectively. 2 nd study HR 67%, renal organ response 41% High-risk patients were less likely to respond to lenalidomide. Lenalidomide/melphalan/dexamethasone HR 58% and CR 42%. The two-year event-free and overall survivals were 54% and 81%, respectively. Lenalidomide/cyclophosphamide/dexamethasone HR 60% in 35 patients, median overall survival was 16.1 months 80% complete response rate in other study. Pomalidomide

40 Bortezomib In an early studies HR 80% HR 77%, with 16% CR Novel Agents the most common side effects were gastrointestinal, with grades 3 and 4 vomiting and diarrhea Weekly regimen showed better toxicity profile bortezomib and dexamethasone after SCT 74% achieved a complete response, with organ responses in 58%. Data from 33 national centers 94 patients receiving bortezomib with or without dexamethasone. Hematologic responses were seen in 71%, 25% complete. A cardiac response was seen in 29% of patients. bortezomib-dexamethasone The overall response rate was 54%, with 31% complete responses. Currently, two studies are under way, one in Europe and one in the United States, randomly assigning patients with newly diagnosed AL amyloidosis to melphalan-dexamethasone or melphalan-dexamethasone-bortezomib.

41 Drug development New drugs in testing MM bendamustine, monoclonal antibodies (IMGN901, CNTO 328, Elotuzumab, MF4809g), histone deacetylase and Hsp90 inhibitors, and new proteasome inhibitors, including irreversible (Carfilzomib) and oral (MLN 9708) formulations. novel drugs that act to inhibit proteotoxicity (the toxic effects of misfolded light chains and aggregates on cells) analogous to the amyloid inhibitors that continue to be developed for Alzheimer s disease. the standardization of adverse-event reporting

42 Autologous stem cell transplant after heart transplant for AL amyloid cardiomyopathy. Heart transplantation followed by SCT is feasible in selected patients with cardiac AL amyloidosis and may confer substantial survival benefit. - In patients presenting with end-stage organ failure, sequential solid organ (kidney, heart, liver) transplant followed by stem cell transplantation (ASCT) has been successfully applied. J Heart Lung Transplant Aug;27(8):823-9.

43 Treatment of AL Amyloidosis off-study Newly Diagnosed AL Amyloidosis Transplant Eligible Transplant Ineligible SCT with Mel Mel-Dex Consider second-line therapy if: heme PR not achieved at day +100 organ progression at 6 months Treat to max response + 2 (no more than 10 cycles) Consider second-line therapy if: heme MR not seen after 4 cycles organ progression at 6 months v1 Jan 2010 Msmart.org